This proposal seeks to establish a CWRU Renal Center. The goal of this Center is to gain a better understanding of the molecular, cellular and genetic basis of kidney failures, laying the groundwork for applications of new methodologies to their treatment. The rationale behind the proposed research program is that a clear delineation of pathophysiological mechanisms is a prerequisite for development of rational treatment strategies. As new drug discovery methodologies are perfected, understanding the molecular basis of renal dysfunction will undoubtedly identify exciting possibilities for treatment of a group of disease with few, effective therapeutic. The Center is composed of five projects, which are linked and supported by a scientific core, the Peptide Biochemistry Core (Core A). Each of the component projects, describe below, addresses the overall goal of the Center. Project 1 (Sendor, Wang) studies mechanisms by which glomerular microenvironment regulates the phenotype of the mesangial cell, which is critically involved in glomerular injury. The goal of Project 2 (Schelling, Haldar) is to define mechanisms of tubular atrophy in progressive kidney disease and will test the hypothesis that hypoxia induces Fas-dependent RTC apoptosis. The hypothesis of Project 3 (Brown, Schwalbe) is K+ flux via ROMK is severely compromised in a variant of Bartter's syndrome and proposes that blocking ROMK will be effective treatment and that ROMK blocks will form a new class of diuertics. Project 4 (Iyengar, Sehgal, Olson) capitalizes on a collaborative initiative between members of the Division of Nephrology and the Department of Epidemiology and Biostatistics to collect family history and medical data from affected, relative pairs and families with ESRD to identify genetic risk factors for ESRD. Project 5 (Carlin) propose studies to define elements of the polarized EGF sorting machinery in epithelial cells to better understand the pathogenesis of polycystic kidney disease. This Center includes, in addition to nephrologist-scientists, a number of outstanding investigators not previously involved in kidney disease research. In summary, the CWRU Renal Center brings together a multi- disciplinary group of investigators to apply state-of-the-art approaches to the analysis and cure of kidney disease within the rich research environment of the CWRU School of Medicine.